Design and Synthesis of Indole-Containing Tetrahydrothiazolo[3,2-<i>a</i>]pyrimidine Mesoionics against Hemipteran Pests

Mesoionic insecticides have emerged as promising pest nAChR modulators devoid of cross-resistance with neonicotinoids, demonstrating exceptional efficacy against sap-feeding insects. Nevertheless, the tetrahydrothiazolo[3,2-<i>a</i>]pyrimidine structure remains underexplored within this chemotype. Here, we report an indole-based scaffold hopping of tetrahydrothiazolo[3,2-<i>a</i>]pyrimidine, which leads to the development of a series of novel mesoionics. Their insecticidal potency is evaluated against the hemipteran pest <i>Acyrthosiphon pisum</i> (<i>A. pisum</i>) and <i>Sogatella furcifera</i> (<i>S. furcifera</i>). Derivative <b>G</b>_<b>1</b> exhibits excellent aphicidal activity (LC₅₀ = 5.11 mg/L), comparable to triflumezopyrim (TFM) (3.71 mg/L) though less than fenmezoditiaz (1.03 mg/L). Chirally resolved (<i><b>R</b></i>)<b>-G</b>_<b>1</b> displays enhanced efficacy against <i>A. pisum</i> (LC₅₀ = 2.12 mg/L). Notably, <b>G</b>_<b>1</b> demonstrates significantly lower acute contact toxicity to honeybees (LD₅₀ = 27.66 μg/bee) versus TFM (highly toxic, 0.66 μg/bee) and fenmezoditiaz (moderately toxic, 5.12 μg/bee). Enzymatic assays, ELISA, and proteomics suggest <b>G</b>_<b>1</b>'s disruptive impacts on neuronal pathways. Molecular docking shows strong binding of (<i><b>R</b></i>)<b>-G</b>_<b>1</b> to <i>Aplysia californica</i> AChBP via hydrogen bonds with residues IleC106, TrpD147, and TyrD195. This study identifies <b>G</b>_<b>1</b> as a potent insecticide lead with favorable pollinator safety.